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• W2327465606 abstract "Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCAberrant activation of Wnt signaling results from stabilization and transcriptional activation of β-catenin and is often associated with carcinogenesis. Clinical evidence suggests that β-catenin accumulation occurs in breast cancer although activating mutations are rare. We have previously shown that Rad6B positively regulates β-catenin stability and transcriptional activity in breast cancer cells by inducing stable polyubiquitin modifications. Here we show that Rad6B physically interacts with β-catenin within the β-catenin amino acid segment containing the first armadillo repeat, which is also a binding site for casein kinase 1 (CK1). β-catenin phosphorylation by GSK3β and subsequent ubiquitination and proteasomal degradation is dependent upon CK1-mediated initiating phosphorylation of β-catenin at Ser45. In vitro kinase assays showed that Rad6B inhibits Ser45 phosphorylation by CK1, and Ser45 phosphorylated β-catenin is decreased in Rad6B overexpressing breast cancer cells. In vitro and in vivo mapping, and site-directed mutation analysis identified K394 of β-catenin as the predominant site for ubiquitination by Rad6B. MCF-7 breast cancer cells engineered to express myc-tagged K394R-β-catenin showed decreased steady-state levels and β-catenin transcriptional activity as compared to cells expressing wild type β-catenin. We also determined whether Rad6B-mediated β-catenin stabilization occurs independently of the canonical Wnt signaling pathway. MDA-MB-231 breast cancer cells overexpressing endogenous Rad6B were isolated on the basis of Rad6B promoter activity, and the consequences of Wnt disruption on β-catenin levels, transcriptional activity and Rad6B expression were determined by expressing a dominant negative mutant of Wnt coreceptor, LRP6. Disruption of Wnt signaling inhibited Rad6B expression and β-catenin accumulation. Both Wnt signaling disruption and Rad6B silencing separately enhanced localization of β-catenin on the cell membranes and decreased intracellular β-catenin accumulation. In summary, our data suggest that the Rad6B overexpression frequently observed in breast carcinomas contribute to β-catenin stabilization and transcriptional activation by inhibiting the CK1-mediated initiating phosphorylation and by ubiquitinating K394. However, the Rad6B induced β-catenin stabilization requires intact Wnt signaling. Supported by DOD W81XWH07-1-0562.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1000." @default.
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• W2327465606 date "2010-04-15" @default.
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• W2327465606 title "Abstract 1000: Rad6B induced β-catenin stabilization requires intact Wnt signaling" @default.
• W2327465606 doi "https://doi.org/10.1158/1538-7445.am10-1000" @default.
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